Breast cancer is one of the leading causes of cancer mortality among Western women, and is predicted to become a leading cause of cancer death in Oriental women in countries such as Japan in the near future. The American Cancer Society estimates that 1 in 9 women face a lifetime risk of this disease, which will prove fatal for about one-quarter of those afflicted with the disease. Breast tumours as well as some other tumours (including uterine cancer, ovarian cancer, endometriosis, uterine fibroids, benign prostatic hyperplasia and melanoma), are known to be estrogen-sensitive, meaning that the formation and growth of such tumours is stimulated by estrogens such as 17β-estradiol. 17β-estradiol is an estrogen that is endogenous to the human body and that is found in both females and males.
Estrogens are known to increase the risk of e.g. breast and endometrial tumours by inducing an estrogen receptor mediated increase in the frequency of breast and endometrial cell division (proliferation). Cell division is essential in the complex process of genesis of human cancer since it per se increases the risk of genetic error, particularly genetic errors such as inactivation of tumour suppressor genes.
An important element of the treatment of estrogen-sensitive tumours, is the suppression or, if possible, elimination of certain estrogen-induced effects. For this purpose, it is desirable to block receptor sites stimulated by estrogens and/or to reduce the amount of estrogen available to act at these sites.
A commonly used therapy to block receptor sites involves the administration of anti-estrogen. Anti-estrogens are a class of chemicals which inhibit estrogens from eliciting their full response in target tissues. An anti-estrogenic compound currently being utilised in the chemotherapy of estrogen-sensitive cancers is tamoxifen. Tamoxifen is a so called selective estrogen receptor modulator (SERM), meaning that the substance exhibits both estrogen antagonist and agonist properties. Although such mixed agonist/antagonists have beneficial effects in the treatment of these cancers, the estrogenic side-effects are also known to have stimulatory effects on certain cancer cell populations in the uterus and therefore, are counterproductive in some cases. SERMs that seem not to display such uterine agonistic effects are also known in the art (e.g. raloxifene), but suffer from the drawback that they can induce climacteric complaints such as hot flushes and sweats. Furthermore, such SERMs have been associated with an enhanced risk of venous thromboembolism, which is another agonistic estrogenic effect.
Reduction of estrogen concentrations in blood serum may be achieved surgically (ovariectomy, adrenalectomy, hypophysectomy) or pharmaceutically through administering high doses of progestogen, GnRH analogue or steroid pathway inhibitors. However, long term suppression of endogenous estrogen production will lead to hypoestrogenism. Furthermore, it is noted that even in the total absence of sex steroids, some receptors may be activated. See Simard and Labrie, “Keoxifene shows pure antiestrogenic activity in pituitary gonadotrophs”, Mol. Cell. Endocrinol. 39: 141-144, (1985), especially page 144.
U.S. Pat. No. 4,937,238 (Lemon) relates to a method of preventing breast cancer in female mammals comprising the steps of administering a compound selected from the group of drugs including (1) 4-OH estradiol; (2) d-equilenin; and (3) 17α-ethinyl estriol. A general formula is provided to describe a set of compounds (1) including 4-OH estradiol. Said formula encompasses a huge variety of estrogen-like substances, including substances that may contain 4 or more hydroxyl groups. With the exception of 4-OH estradiol no other representative of this large group of substances are discussed.
U.S. Pat. No. 5,340,584 (Spicer et al.) describes a method for preventing conception or for treating benign gynecological disorders comprising administering a GnRH composition for a first period of time in an amount effective to suppress ovarian estrogen and progesterone production, simultaneously administering an estrogenic composition in an amount effective to prevent symptoms of estrogen deficiency and simultaneously administering a progestogen in an amount effective to maintain serum level of said progestogen at a level effective to decrease endometrial cell proliferation. The US patent is primarily concerned with slow release formulations that are effective over an extended period of time of at least about two months. In a long list of estrogens that can be used in the claimed invention estetrol is mentioned.
WO 02/30355 (Kragie) describes a method of alleviating adverse side effects and/or enhancing the beneficial efficacy of an aromatase inhibitor in a subject, wherein said method comprises administering a combination of one or more aromatase inhibitors with one or more estrogen function replacement agents (EFR). A wide array of EFR agents are recited in the application, including estrogens. In a list of estrogens also estetrol is mentioned. The claimed method is said to be beneficial for treating subjects suffering from side effects and reduced therapeutic benefit of compositions comprising an aromatase inhibitor administered as a therapeutic for a large variety of disease states or clinical indications. In relation to breast cancer, which is mentioned as an example of a disease state, it is observed that aromatase inhibitors are used to diminish the production of estrogens at the site of cancerous breast tissue. Selective EFR agents such as raloxifene and estradiol metabolites are said to be beneficial as an EFR agent in tumor therapy. As regards estradiol metabolites, reference is made to an article by Lippert T H, et al. Steroids 2000; 65:357-69. Said article reports the results of a study into the effects of A-ring and D-ring metabolites of estradiol, including estetrol, on the proliferation of vascular endothelial cells. The results show that some A-ring metabolites are capable of inhibiting proliferation of cultured endothelial cells of human umbilical cord veins. No significant effect was observed for estetrol.
Estrogen antagonists will usually produce better therapeutic results than therapy which only inhibits estrogen production, e.g. GnRH analogues, aromatase inhibitors and/or progestogens. Consequently, there is a need for a drug that exhibits a more favourable combination of agonistic and antagonistic (or non-agonistic) properties than the anti-estrogens and/or SERMs that are currently available. In particular, there is a need for a drug which does not have undesirable proliferative effects on breast and/or endometrial tissue and which, at the same time, displays sufficient estrogenicity to prevent that its administration will lead to hypoestrogenism and/or climacteric complaints.